The yeast genes IXR1 and HMO1 encode proteins belonging to the family of chromatin nonhistone proteins, which are able to recognize and bind to irregular DNA structures. The full deletion of gene IXR1 leads to an increase in cell resistance to the lethal action of UV light, gamma-rays, and MMS, increases spontaneous mutagenesis and significantlly decreases the level of UV-induced mutations. It was earlier demonstrated in our works that the hmo 1 mutation renders cells sensitive to the lethal action of cisplatin and virtually does not affect the sensitivity to UV light. Characteristically, the rates of spontaneous and UV-induced mutagenesis in the mutant are increased. Epistatic analysis of the double mutation hmo 1 ixr1 demonstrated that the interaction of these genes in relation to the lethal effect of cisplatin and UV light, as well as UV-induced mutagenesis, is additive. This suggests that the products of genes HMO1 and IXR1 participate in different repair pathways. The ixr1 mutation significantly increases the rate of spontaneous mutagenesis mediated by replication errors, whereas mutation hmo 1 increases the rate of repair mutagenesis. In wild-type cells, the level of spontaneous mutagenesis was nearly one order of magnitude lower than that obtained in cells of the double mutant. Consequently, the combined activity of the Hmo 1 and the Ixr1 proteins provides efficient correction of both repair and replication errors.

The review deals with cyclodepsipeptides produced by hyphomycetes. The cyclodepsipeptide compounds are prospective new agents for the treatment of diseases of the infectious and pathophysiologic nature.

Novel 2,3-seco-triterpenic amides were prepared by the interaction of the chloride of 2,3-seco-l-cyano-19beta,28-epoxy-18alpha-oleane-3-oic acid with primary amines and synthetic and biogenic amino acids. A cytotoxic triterpenic conjugate with a residue of the ethyl ester of beta-alanine was found among the synthesized nitrogen-containing derivatives. Treatment with this conjugate in a concentration of 100 muM resulted in the 45.5% survival of melanoma cells in the medium.

Identification of proteins that can be therapeutically targeted is an important problem in molecular biology. Transcriptomics approaches such as coexpression network analysis have been previously proposed as tools facilitating drug targets discovery. To assess whether coexpression network analysis is applicable to prediction of novel anticancer drug targets, we compared known targets of 103 antineoplastic drugs with those of 776 drugs irrelevant to cancer in terms of their position in the coexpression network of glioblastoma--one of the most malignant human cancer types. Affymetrix GeneChip expression data for 93 glioblastoma surgery samples were analyzed. We were able to identify coexpression modules associated with such processes as proliferation, immune response, neurotransmission, ATP synthesis, extracellular matrix formation and others. Anticancer drug targets were fourfold over-represented in the coexpression module associated with cell proliferation and mitosis relative to the other modules. Network connectivity of drug targets within the mitotic module was found to be highly correlated with the number of anticancer drugs acting upon them. Our results support the hypothesis that hubs in the mitotic module represent potential anticancer drug targets, and confirm applicability of coexpression network analysis to anticancer drug targets identification.

Small interfering RNAs (siRNA) are considered to be potent agents for specific gene silencing, but troubles in delivery of siRNA into cells limit their biomedical application. An accumulation of siRNA coupled with cholesterol residue at the 5'-end of the "passenger" strand (chol-siPHK) was investigated in HEK293, HepG2, SC1, and KB-8-5 cells. In the absence of a transfectant levels of both unmodified and chol-siRNAs were very low, whereas transfectant substantially increased transfection rate in all cell lines; in HEK293, SC1, and KB-8-5 cells transfection efficiency for the chol-siRNA being higher than that for the corresponding siRNA. Multiple drug resistance phenotype reversing activity of anti-MDR1-siRNAs targeted to the 557-577 region of MDR1 gene mRNA was investigated in KB-8-5 cancer cells. The chol-siRNA induced cancer cells' death in the presence of vinblastine doses tolerated before more effectively than the conventional siRNA did.

Multiple drug resistance (MDR) of tumor cells to cytostatics is one of the most often and severe complications of chemotherapy in oncological patients. The phenomenon of MDR could be due to a sharp increase of the activity of the ATP-dependent transport proteins of the ABC system, that provides pumping of the drug from the cells to the extracellular space. Up to now, all the attempts to design agents preventing MDR were of no success. One of the prospective trends is the use of hydrophilic regulator hexapeptides. Three regulator hydrophilic hexapeptides of the linear and cyclic structure were used as the MDR modulators. The sensitivity of the tumor cells to various cytostatics in the presence of the peptides was determined by the MTT-test and the direct counting of the survived cells. The effect of the hexapeptides on MCF7, KB8-5 and PC3 cells was investigated. It was concluded that the hydrophilic hexapeptides of the linear and cyclic structure increased the sensitivity to doxorubicin (a cytostatic). The tumor cell MDR inhibition was mediated by the ATP-dependent transport protein MRP. Such a characteristic of the hexapeptides is of interest for their use as agents preventing MDR.

Toxicologic characteristics of anti-tumor medication lisomustine. The authors presented materials on experimental studies of toxicity and jeopardy to justify hygienic regulation of workplace air for antitumor medication lisomustine: data on acute toxicity, results of irritative, resorptive and sensitizing effects evaluation, mutagenous and cumulative effects, influence on reproduction.

Experiments on guinea pigs with the use of electrophysiological methods (short-latency auditory evoked potentials, SLAEPs, and distortion product otoacoustic emission, DPOAE) have demonstrated damage of outer hair cells following application of therapeutic doses of cisplatin. It is concluded that finding of the logarithmic amplitude-time dependence for the first SLAEPs peak permits to diagnose an injury to outer hair cells.

Data are presented on a retrospective comparison of the results of remote radiotherapy and combined treatment of prostate cancer (T2T4NxM0) (88) at the Center's Clinics (1999-2003). Diagnosis was confirmed by morphological evidence: T2NxM0 (group 1)--18.2%, T3aNx M0 (group 2)--53.4%, T3bNx M0 (group 3)--18.2%, T4NxM0--10.2% (group 4). In group 1 (n=37), contemporary radiotherapy was administered--TTD--up to 44 Gy (stage I) and up to 66-70 Gy (stage II). In group 2 (n=51), contemporary radiotherapy was supplemented with inhalation of radioprotector GGS-9--TTD--up to 44 Gy plus GGS-9 (stage I) and up to 72-76 Gy plus conformaton radiotherapy (3D CRT) (stage II). When GGS-9 was used at stage I the rate of acute radiation injury dropped from 56.7% in group 1 to 11.7% in group 2, (p=0.0001). The frequency of late-onset injury was also lower in patients receiving 3D CRT (13.5 and 3.9%, respectively) (p=0.01). Local and biological relapse occurred frequently after contemporary radiotherapy (27%) as compared with conformation one (5.8%). The latter treatment was followed by higher 5-year recurrence-free survival (94.2%) as compared with contemporary radiotherapy (73%), (p=0.0001). Owing to use of 3D CRT, dose distribution was improved as volume and dosage for organs at risk of irradiation decreased, while TTD increased up to 72-76 Gy unaccompanied by a rise in early-onset injuries. On the contrary, late-onset radiation damage fell down.

When used separately, diethylnitrosamine (DENA) initiates 4-6 times more neoplastic lesions in the liver of suckling mice than ortho-aminoazotoluene (OAT) lower. However, after combined treatment with either carcinogen the total number of hepatic lesions was significantly than that in mice injected with DENA only. Similar inhibition of DENA-induced hepatocarcinogenesis was observed when OAT was administered 8-12 hrs after DENA. Our findings cannot be adequately explained except by competition of the carcinogens for supposedly target molecules of protein origin, presumably, transcription factors, which contribute to generation of genetic information. They have different affinities for different compounds and, therefore, suffer different damage from the latter functioning.

Previously, significant increase in survival in locally-advanced rectal cancer as a result of heated intraoperative intraperitoneal chemotherapy was reported. Our study used cisplatin 0.5 mg/ml (0.05 per cent solution) in the culture of pharyngeal epidermoid carcinoma (PEC) cells (HEP-2) and A-549 culture of lung carcinoma cells. The number of viable cells was estimated colorimetrically after 24 and 48 hr incubation. 50%-rise in inhibition of culture growth was assumed to be biologically significant. Forty-eight hours after inoculation, single dose of cisplatin 8 mg/kg was injected in mice bearing transplanted lung carcinoma of Lewis (LLC). That was followed by death of tumor cells. Preheating (45 deg. C, 1 hr) did not influence either the cytostatic or therapeutic effect of cisplatin in vivo.That procedure inhibited tumor growth by 7-8% and the effect did not wear off until day 11 or longer. Survival in LLC-bearing mice rose by 26% which pointed to the advantages offered by heated cytostatic chemotherapy.

The Ad5-Lf recombinant pseudoadenovirus nanostructure (RPAN) based on adenovirus of the 5th serotype and containing lactoferrin (Lf) gene was constructed. The goal of this work was to develop a system for efficient production of human lactoferrin (Lf) in human body. It was shown using the model of cisplatin (DDP)-induced toxicosis that human Ad5-based RPAN with human Lf gene expressing cassette in its genome provides high rate of expression of Lf gene in animal body. In vivo recombinant human Lf demonstrates detoxification effect against acute DDP-induced toxic reactions similar to that of the native Lf. RPAN does not stimulate growth of primary and metastatic nodes of experimental tumors. Moreover, it inhibits the growth of Lewis lung carcinoma (LLC), Ehrlich carcinoma (ELD), and S37 sarcoma in early periods after tumor transplantation. The obtained experimental data are indicative of the good prospects of further biologic and medical study of RPAN and development of RPAN-based genetic engineering medicine of the new generation.

Four polyhydroxylated steroids, new (20R)-5alpha-cholestan-3beta,6alpha,8,15alpha,24,26-hexaol (I) and known (20R,25S)-5alpha-cholestan-3beta6alpha,8,15beta,16beta,26-hexaol, (20R,25S)-5alpha-cholestan-3beta,6alpha,15beta,16beta,26-pentaol, and marthasterone sulfate were isolated from the Solaster endeca starfish inhabiting the Sea of Okhotsk and characterized. Steroid (I) contains a 24,26-dihydroxylated side chain, which is uncommon for starfish polyols. The isolated steroids and related metabolites from two starfish species of the Evasterias genus (in total, 15 compounds) were weakly cytotoxic in a human HeLa cell culture and some of them were inhibitors of nonspecific esterase from mouse Ehrlich carcinoma. The effects of these compounds on the p53 protein activity were studied in a yeast two-hybrid test system and both inhibitors and stimulators of this activity were found among them.

Results of a comparative study of the influence of doxorubicine (DOX) and dehydroepiandrosterone (DHEA) on cell proliferation and oxidative stress in Saccharomyces cerevisiae cells are presented. Three treatment schedules were assessed--DOX only, DHEA only, and DOX simultaneously with DHEA--in examining cell proliferation, measuring the content of glutathione, and evaluating the expression of ribonucleotide reductase in the test cells. The results indicate that the separate treatment with DOX or DHEA stimulates the expression of ribonucleotide reductase and leads to a decrease in the rate of cell proliferation. DHEA produces a dose-dependent decrease in the content of a reduced form of glutathione in cells, whereas the concentration of the oxidized form remains unchanged. In contrast, the treatment with DOX increased the concentrations of both forms of glutathione. The simultaneous treatment of cells by DOX and DHEA increased the accumulation of intracellular glutathione and decreased the total antiproliferative effect.

Experiments on C57B1/6 mice showed that ginsenoside Rh2 inhibited the growth and metastasis process of Lewis lung tumor and increased the antitumor and antimetastatic effects of cyclophosphamide. On the model of transferred melanoma B-16, ginsenoside Rh2 showed a tendency to increase the antiblastome effect of the cytostatic drug.

The results of Allium-test screening of new 2,4- and 2,6-dinitroaniline derivates on antimitotic activity and phytotoxicity are presented in the work. It is revealed that all studied compounds which are derivates of 2,4-dinitroaniline, 2,6-dinitro-(4-fluoromethyl)-aniline as well as (methylsulfonyl) nitrobenzol, can evoke a change in mitotic index value, an appearance of cytogenetic damages and also have phytotoxic effect on Allium cepa seedling roots. On data obtained the continuation of investigation the action of N-(2,4-dinitrophenyl)-orto-aminobenzoic acid, N,N-diethyl-2,6-dinitro-4-(trifluoromethyl)-aniline and 1-methylsulfonyl-3-nitrobenzol as potential herbicides is proposed.

The action of two types of substances has been studied: 5-azadeoxycytidine and retinoic acid, which have a demethylation effect on DNA in the development process of diploid parthenogenetic mouse embryos. The effect of 5-azadeoxycytidine on hybrid mice (CBAxC57BL/6)F1 in vitro for 6 h, in the presence of single cell parthenogenetic embryos during the S-phase of the cell cycle has been studied. After developing to the blastocyst stage in vitro, parthenogenetic embryos were transplanted into the uterus of false pregnant females. It has been determined that a concentration of 0.1 microM 5-azadeoxycytidine activates embryonic development in the preimplantation period until the blastocyst stage (69% in experiment; 61% in the control) and during postimplantation, it increases the number of available space in the uterus for implantation (76% in experiment; 63% in the control). The effect of retinoic acid on parthenogenetic embryos from inbred C57BL/6 or CBA mice lines was studied by adding it to single cell embryos in a medium in vitro for 96 h. Treating parthenogenetic embryos C57BL/6 with retinoic acid concentrations 0.1 microM or 0.5 microM significantly increased the number of spaces for embryo implantation, 76% and 78% respectively, as against 57% for untreated embryos. Addition of similar doses of retinoic acid to the nutrient medium containing CBA parthenogenetic mouse embryos does not improve implantation (as with embryos C57BL/6), and a concentration of 2.0 microM is toxic to the embryos. During the period of postimplantation, parthenogenetic embryos of mouse lines C57BL/6 treated with retinoic acid just as the controls, did not develop to the somite stage. Mouse lines CBA had 45% of their embryos which were used as controls, developing to the advanced somite stages. However, the number of embryos treated with retinoic acid does not increase. Thus the treatment of two parthenogenetic embryos from inbred mice lines and their hybrids with compounds which demethylate DNA (5-azadeoxycytidine and retinoic acid) creates an opportunity for partial modulation of genomic imprinting and an increase in the survival rate of such embryos.

Effect of the antiserotonin drug cyproheptadine on the erythropoiesis has been studied under conditions of the administration of cytostatics (fluoropyrimidine antimetabolite 5-fluorouracil (5-FU), alkylating agent cyclophosphane) with different mechanisms of action. It is established that the antiserotonin drug significantly accelerates regeneration of the erythroid hemopoietic branch, especially in the case of 5-FU. The depression of erythron under the conditions of cyclophosphane injections was retained. The erythropoiesis-stimulating effect of cyproheptadine is based on the restoration of the structural and functional organization of the bone marrow (formation of erythroid hemopoietic islets).

The use of imatinib mesylate (Glivec) (Novartis Pharma AG, Switzerland) that is the drug of choice in treating patients with chronic myeloid leukemia (CML) has increased 7-year survival and improved the prognosis of the disease. The drug is generally tolerated well; the proportion of patients in whom imatinib treatment results in the development of toxic complications is small. Drug-induced interstitial pneumonitis associated with imatinib therapy is a rare complication that requires timely differential diagnosis, discontinuation of an inductor (imatinib), and altered further treatment policy.